tbuckley/cabot-search huggingface dataset:
Determining MSI status by a one-step PCR melting curve analysis of Chinese-specific mononucleotide repeats.
Authors: Huang Chen, Jianzheng Jie, Ruiying Jiang, Xiaowei Wang, Ye Wang, Qianqian Feng, Yun Niu, Bei Wang, Jie Luo, Wenqing Su, Youcai Li, Fei Gai, Roman Song, Changbin Zhu, Dingrong Zhong
Journal: Journal of Clinical Oncology (2023)

e15532 Background: Microsatellite instability (MSI) is a hypermutated phenotype primarily caused by the deficiency of DNA mismatch repair activity. Conventional MSI detection platforms are time consuming and need extra normal tissue. Due to the short DNA sequences of microsatellite loci in MSI samples, the method can be simplified to a one-step approach to differentiate MSI status by observing the melting curve. Herein a novel feasible MSI status detection method based on one step-PCR in single tumor tissue was developed, and validated in colorectal cancer samples. Methods: Specific microsatellite sites shorter than 12 bp in length (feasibility of fluorescence probes) were selected from public databases for analysis. In tumor tissues from 98 CRC patients with known MSI status, microsatellite sites with the highest receiver operating characteristic (ROC)-area under the ROC curve (AUC) were eventually selected for the final PCR panel design. The cut-off value of this assay was defined by the number of melting peaks in a specific Tm value range. An independent set of 199 tumor tissues from CRC patients with known MSI by Sanger sequencing was recruited to validate the performance of this novel PCR MSI kit. Results: The ROC-AUCs of the pre-selected eight mononucleotide repeats were 0.82, 0.93, 0.79, 0.78, 0.98, 0.95, 0.92, and 0.79. When 0 or 1 marker had a melting peak within the specified Tm value range, the sample was identified as "MSS/MSI-low (MSI-L)"; when 2 or more markers had melting peaks within the specified Tm value range, the sample was determined to be "MSI-high (MSI-H)". In the clinical sample set, compared with the results given by conventional MSI detection method, the sensitivity of the 8-gene panel for MSI-H was 99.4% (166/167), the specificity of the 8-gene panel was 100%, and the overall concordance reached to 99.5%. Conclusions: The novel PCR-MSI detection method using 8-gene panel developed in this study was feasible and accessible in clinical practice, and a large-scale clinical validation is in progress. [Table: see text]
Genomic alterations of cerebrospinal fluid cell-free DNA in leptomeningeal metastases of gastric cancer.
Authors: Xin Chen, Kaixuan Bai, Yu Zhang, Yang Xu, Yinghao Huo, Sha Wang, Yueli Zou, Xuejiao Qi, Rongyun Guo, Qiuxiang Ou, Minyi Zhu, Dengxiang Liu, Shaohua Yin, Shubo Chen, Hui Bu
Journal: Journal of Clinical Oncology (2023)

e16022 Background: Leptomeningeal metastases (LM) were rare in gastric cancer (GC), and GC patients with LM (GCLM) generally suffer from poor prognosis. Nevertheless, the clinical utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) was under-investigated in GCLM. Methods: We retrospectively studied 15 GCLM patients, and all patients had paired primary tumor tissue samples and post-LM CSF samples while 5 patients also had post-LM plasma samples. All samples were analyzed using next-generation sequencing (NGS), and the molecular and clinical features were correlated with clinical outcomes. Results: CSF had higher mutation allele frequency ( P=0.015), more somatic mutations ( P=0.032), and more copy-number variations ( P&lt;0.001) than tumor or plasma samples. Multiple genetic alterations and aberrant signal pathways were enriched in post-LM CSF, including CCNE1 amplification and cell cycle-related genes, and CCNE1 amplification was significantly associated with patients’ overall survival ( P=0.0062). More potential LM progression-related markers were detected in CSF samples than in tumor samples, including PREX2 mutation ( P=0.014), IGF1R mutation ( P=0.034), AR mutation ( P=0.038), SMARCB1 deletion ( P&lt;0.001), SMAD4 deletion ( P=0.0034), and TGF-beta pathway aberration ( P=0.0038). Additionally, improvement in intracranial pressure ( P&lt;0.001), improvement in CSF cytology ( P=0.0038), and relatively low levels of CSF ctDNA ( P=0.0098) were significantly associated with better PFS. Lastly, we reported a GCLM case whose CSF ctDNA dynamic changes were well correlated with his clinical assessment. Conclusions: CSF ctDNA could more sensitively detect molecular markers and metastasis-related mechanisms than tumor tissues in GCLM patients, and our study sheds light on utilizing CSF ctDNA in prognostic estimation and clinical assessment in GCLM.
A randomized study of consolidation chemoradiation (CTRT) vs observation after first-line chemotherapy (CT) in advanced gall bladder cancers (GBC): RACE-GB Study.
Authors: Sushma Agrawal, Rahul Rahul, Ashish Singh, Prabhakar Mishra, Rajan Saxena
Journal: Journal of Clinical Oncology (2023)

4016 Background: CT (gemcitabine plus cisplatin) is the standard of care for patients presenting with unresectable advanced GBC but their prognosis remains poor. The value of CTRT after CT is uncertain. We therefore conducted a randomised trial evaluating consolidation CTRT versus Observation after four cycles of CT in those patients whose disease did not progress during CT (NCT05493956). Methods: Responders (partial response and stable disease) to 4 cycles of CT were randomised to CTRT vs observation (n=135). CTRT was delivered by 3D-Conformal Radiation Therapy along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. The primary endpoint was overall survival which was calculated from the date of randomisation. The trial is designed to detect an improvement in 2-year OS from 8% in the control arm to 25% in study arm with 80.0% power at a 0.05 significance level. The required sample size was 130 (65 in each arm) over a duration of 4-5 years. CTRT was delivered by 3DCRT along-with concurrent capecitabine @1250 mg/m2. The dose of RT was 45Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. Toxicities documented during CT and CTRT were recorded using the CTCAE version 3.0. and RTOG criteria respectively. Chi square test and Survival analysis was performed for the data analysis. Demographic data and CTRT Dose volume data were correlated with side effects and survival. Statistical analysis was performed with SPSS version-23. Results: 67 patients were randomized to observation and 68 to CTRT. Their demographic characteristics were well balanced. 63% were women, 58% had T4 tumours, 42% had N2, 27% needed stenting for obstructive jaundice. The median overall survival in the CTRT arm was 10 months versus 4 months in the observation arm (HR 0.47 [95% CI 0.33-0.68] p=0.001). Adverse events (grade 3 or higher) due to CTRT included the following: Nausea 3%, Anemia 9%, GI bleed 6%, hepatotoxicity 13%. Updated survival data and prognostic factors affecting overall survival will be presented in the meeting. Conclusions: CTRT after 4 cycles of CT significantly prolonged overall survival but was also associated with adverse events. Clinical trial information: NCT05493956 .
Androgen receptor–specific CD8+ T cells with tumor cell cytotoxicity in patients with prostate cancer in Taiwan.
Authors: Wilson Huang, Tzu-Ping Lin, William J. Huang, Chia-Jen Wu
Journal: Journal of Clinical Oncology (2023)

e17069 Background: Classical androgen receptor (AR) target is the new “tumor-specific” antigen for prostate cancer vaccine development to delay progression and castration-resistant disease. HLA-A2-restricted AR ligand-binding domain (LBD) has been demonstrated to stimulate cytotoxic T lymphocytes (CTL) in HLA-A2+ prostate cancer patients. Although the prevalence of HLA-A2 serotype and LBD-specific CD8+ T cells among Caucasians are known, their frequencies in the Taiwan patients have not been established. In this study, we performed HLA-A2 genotyping, HLA-A2+ LNCaP stimulation of autologous T cell, and CTL tumor cell cytotoxicity from 25 castration-sensitive prostate cancer patients using blood samples collected from a single hospital center. Methods: 20ml whole blood samples are collected in EDTA tube from non-metastatic, castration-sensitive prostate cancer patients. PBMCs are subjected to HLA-A2 allele sequencing, separated by CD3 magnetic bead column, and expanded and activated ex vivo using CD3/CD8 polymeric beads. Autologous T cells are then isolated by CD8 magnetic bead column, stimulated by HLA-A2+ lentivirus-transduced LNCaP (AR+), and targeted against transduced (HLA-A2+) and non-transduced (HLA-A2-) LNCaP (AR+) by Chromium-51 Release Assay. We identified and correlated their frequencies with patient’s age at diagnosis, Gleason grades, PSA level, and family history. Results: A total of 25 blood samples were tested and analyzed for HLA-A2 genotype with 44% (11/25) positive for the HLA-A2 [28% (7/25) heterozygotes, 16% (4/25) homozygotes]. Among the 11 HLA-A2+ patients, 72% (8/11) were HLA-A*02:07 allele, 100% (11/11) CD8+ T cells were successfully stimulated with HLA-A2+ transduced LNCaP (AR+) and 45% (5/11) patients demonstrated HLA-A2+ AR-specific CTL tumor cell lysis. No clinical association with patient age (54-86 y.o.), Gleason grades (6-9), PSA level (3.84-62.8 ng/ml), and family history (1/25). Conclusions: In this single hospital center study, we observed a similar prevalence of HLA-A2 alleles in Taiwan prostate cancer patient cohort with a predominant HLA-A2*02:07 allele, and higher frequencies of HLA-A2-restricted CD8+ T cell stimulation and HLA-A2+ AR-specific tumor cell cytotoxicity. Our findings support the application of AR LBD as tumor antigen for prostate cancer vaccine development for Taiwan prostate cancer patients.
FOOTPATH: A randomized, open-label phase-2 study of liposomal irinotecan + 5-FU and folinic acid (NAPOLI) versus sequential NAPOLI and mFOLFOX6 versus gemcitabine/nab-paclitaxel in treatment-naïve metastatic pancreatic cancer (mPDAC).
Authors: Benedikt Westphalen, Tobias Gaska, Maximilian Reichert, Michael Quante, Helmut Oettle, Dirk Thomas Waldschmidt, Anke Schlenska-Lange, Stefan Angermeier, Ludwig Fischer von Weikersthal, Wolfram Bohle, Ursula Vehling-Kaiser, Arndt Stahler, Stephan Kanzler, Christof Lamberti, Uwe Pelzer, Marianne Sinn, Wolfgang Blau, Stefan Hubert Boeck, Swantje Held, Volker Heinemann
Journal: Journal of Clinical Oncology (2023)

4021 Background: The optimal first-line regimen in the treatment of mPDAC remains unknown. Recent data demonstrated superiority of 5-FU/liposomal irinotecan/oxaliplatin (NALIRIFOX) over gemcitabine/nab-paclitaxel. However, the question remains open if both irinotecan and oxaliplatin are required in first-line treatment and whether these agents can be given sequentially. Methods: Eligible patients with histologically confirmed diagnosis of mPDAC were randomized 1:1:1 to receive in Arm A standard treatment (gemcitabine 1000 mg/m 2 + nab-paclitaxel 125 mg/m 2 ) or investigational therapy applying in Arm B the NAPOLI regimen (liposomal irinotecan 80 mg/m 2 + folinic acid 400 mg/m 2 + 5-FU 2400 mg/m 2 ) or in Arm C a sequence of NAPOLI and mFOLFOX6 (oxaliplatin 85mg/m 2 + folinic acid 400mg/m 2 + 5-FU 2400 mg/m 2 ). Overall, 274 patients were enrolled at 48 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate, disease control rate, duration of study treatment and safety. Results: In the full analysis set (n=265), neither treatment with NAPOLI (3.1 months, HR 1.224, p= 0.2123) nor the sequence of NAPOLI and mFOLFOX6 (6.0 months, HR 0.864 p= 0.0720) lead to a statistically significant improvement of PFS over gemcitabine/nab-paclitaxel (4.3 months). Median duration of treatment was 3.5 months in Arm A, 2.0 months in Arm B and 3.7 months in Arm C, respectively. In a first analysis of overall survival, OS in Arm A was 8.7 months (95% CI, 7.1-11.9 months) versus 7.9 months in Arm B (95% CI, 6.6-12.3 months; HR 1.178, P= 0.348) and 11.0 months in Arm C (95% CI, 8.4-13.6 months; HR 0.879, P=0.154). Overall, safety was comparable with published data, with higher rates of neutropenia and peripheral neuropathy in Arm A, while diarrhea was more frequent in Arms B and C. Conclusions: The study did not show superiority of either NAPOLI or the sequence of NAPOLI/mFOLFOX6 over standard therapy with gemcitabine/nab-paclitaxel. In view of the published evidence, the present data supports the hypothesis that sequential NAPOLI/mFOLFOX6 may be equally effective with regard to OS, but less toxic, compared to mFOLFIRINOX. Clinical trial information: NCT03487016 . [Table: see text]
Retrospective evaluation of erlotinib and gefitinib used in the military health system from the perspective of drug-drug interactions.
Authors: Karen J Shou, Thu-Lan T. Luong, Chelsea N. Powers, Brian J. Reinhardt, Mike J. McAnulty, Peter J. Weina
Journal: Journal of Clinical Oncology (2023)

e15108 Background: Erlotinib and gefitinib are epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) approved primarily for non-small cell lung cancer treatment, with pharmaceutical drug-drug interactions (DDIs) that are vague and poorly understood. Previous studies show that concomitant use of EGFR-TKIs with fluoxetine or losartan results in inhibition of both fluoxetine and losartan. Since DDIs can cause significant clinical ramifications, drugs that may interact with erlotinib or gefitinib must be identified. Methods: Data review was performed by Military Health System (MHS) data experts with data provided by the Joint Pathology Center (JPC) from the Department of Defense (DoD) Cancer Registry, the comprehensive ambulatory/professional encounter record (CAPER) and the pharmacy data transaction service (PDTS). Patients treated for cancer were identified, and the CAPER database was used to identify comorbidities. The PDTS database identified prescription drugs filled during erlotinib/gefitinib use, for all cancers. Patients were sorted into subgroups, (1) completed treatment (erlotinib or gefitinib was the last drug that patients completed, without recorded side effects), or (2) discontinued treatment (patients were treated with erlotinib or gefitinib but had recorded side effects and/or switched treatment). PDTS data and retrospective analysis of encounter notes, were used to sort medications into those that were taken before or after (“.”, “,”, “/”, or space between drugs) and those that were taken at the same time (“+”, “-/+”, or “and” between drugs). Results: 348 patients had diagnosis data, with 234 patients having completed treatment and 114 patients having discontinued treatment. Patients who discontinued treatment were diagnosed with more health issues than patients who completed treatment. A total of 258 patients had pharmacy data filled for erlotinib (240 patients) or gefitinib (18 patients). Of these, 177 patients completed treatment and 81 patients discontinued treatment. Patients in the completed treatment group filled 1 to 75 drugs, median range 11-20 drugs. Patients in the discontinued treatment group filled 3 to 103 drugs, median range 31-40 drugs. Patients who discontinued treatment filled more drugs than patients who completed treatment. The 20 most filled drugs, associated with side effects during erlotinib or gefitinib usage and the specific associated side effects were identified. Conclusions: This review cannot conclude that any drug resulted in erlotinib or gefitinib discontinuation. However, associations between top filled drugs and side effects have been made. Proof of concept in vitro laboratory testing should be done with these identified drugs, to confirm mechanistic interactions that may lead to clinical effects.
Outcomes of patients (pts) with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who progressed to metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TRUMPET registry.
Authors: Daniel H. Shevrin, James Thomas Symanowski, Neal D. Shore, Daniel W. Lin, David Russell, Pavol Kral, Yi Song, Nader N. El-Chaar, Lawrence Ivan Karsh
Journal: Journal of Clinical Oncology (2023)

e17085 Background: Significant lack of treatment (Tx) intensification is seen in clinical practice for pts with mHSPC until progression to mCRPC. The TRUMPET registry enabled a post-hoc analysis of clinical outcomes in pts with mCRPC, initially diagnosed with de novo mHSPC vs nmHSPC. Methods: TRUMPET, a prospective, observational study of US pts with CRPC, enrolled male adults (03/2015-09/2018) who began first or second-line Tx for M0/M1 CRPC. For this post hoc, pts with M1 CRPC at enrollment initially diagnosed with de novo mHSPC (clinical TNM1 stage) were compared to M1 CRPC pts initially diagnosed with nmHSPC (clinical TNM0 stage). Clinical outcomes (radiographic progression-free survival [rPFS], prostate specific antigen [PSA] progression, time to opiate initiation [OI], mortality) were analysed with Kaplan–Meier and Cox proportional hazards models. An exploratory subanalysis investigated outcomes in de novo mHSPC pts who received Tx intensification (docetaxel or abiraterone) with androgen-deprivation therapy (ADT) as primary Tx prior to mCRPC vs pts who did not. Results: M1 CRPC pts initially diagnosed with de novo mHSPC (n = 199) or nmHSPC (n = 254) were included; median age: 70.0 vs 73.0 years, duration from initial PC diagnosis to baseline mCRPC visit: 1.62 vs 6.72 years, PSA at PC diagnosis: 113.1 vs 10.1 ng/mL, Gleason score: 9.0 vs 8.0, respectively. In the de novo mHSPC and nmHSPC groups, initial CRPC Tx was chemotherapy in 9.0% vs 5.9% of pts, novel hormonal therapy (enzalutamide or abiraterone) in 55.3% vs 59.1%, immunotherapy in 35.2% vs 42.9%, respectively. No differences were seen in rPFS or PSA progression (table). The de novo mHSPC group showed a trend toward shorter time to OI and significantly increased risk of mortality (37%) with 6.6 months shorter median survival vs nmHSPC. The subanalysis included 44 (22.1%) de novo mHSPC pts who received Tx intensification with ADT at initial diagnosis. A trend towards improved survival was seen in the Tx-intensified vs nonintensified subgroup (median time to death [95%CI]; 47.7 months [22.18, NE] vs 37.3 months [28.35, 43.01]). Conclusions: At mCRPC diagnosis, pts with de novo mHSPC have significantly higher mortality risk than pts with nmHSPC, indicating a need to delay progression of de novo mHSPC to mCRPC. The trend for improved survival benefit in pts with Tx-intensified de novo mHSPC further underlines the need for early Tx intensification. [Table: see text]
Immunohistochemical expression of ER and p53 as predictive biomarkers of immunotherapy in endometrial cancer.
Authors: Michael Liontos, Aristea-Maria Papanota, Anna Svarna, Vasileios Pergialiotis, Oraianthi Fiste, Christos Markellos, Elena Kunadis, Eirini Potiri, Angeliki Andrikopoulou, Alkistis Papatheodoridi, Konstantinos Koutsoukos, Maria Kaparelou, Kalliroi Goula, Kitty Pavlakis, Nikolaos Thomakos, Dimitrios Haidopoulos, Alexandros Rodolakis, Flora Zagouri, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2023)

e17626 Background: Immune Checkpoint Inhibitors (ICIs), either as monotherapy or in combination with tyrosine kinase inhibitors (TKIs), were recently incorporated into the therapeutic guidelines for recurrent/metastatic endometrial cancer (EC). Microsatellite Instability (MSI) is the only biomarker to guide treatment. We evaluated the predictive significance of Estrogen Receptor (ER) and p53 expression. Methods: Medical charts of EC patients that received ICIs in our institution for advanced/metastatic disease were retrospectively reviewed. TP53 and ER expression were determined by immunohistochemistry. Survival analysis was performed using IBM SPSS statistics v.25. Results: Thirty-two patients were included in our analysis. The median age was 63.1 years (25 th -75 th percentile: 57.6 – 69.6). 62.5% of the patients had endometrioid histology, 21.9% serous histology and 15.6% of them displayed other histology. 46.9% of the patients had grade 1-2 tumors and 53.1% grade 3 tumors. 21.9% of them were diagnosed with stage 1-2 disease, while 78.1% presented with stage 3 disease. 62.5% received 0-1 prior lines of treatment and 37.5% of them received more than 2 prior lines. Molecular characteristics are presented in the table. All MSI-High patients received anti-PD1 monotherapy with a median PFS of 11.9 months (95% CI:2.3-21.5). Microsatellite Stable (MSS) patients received pembrolizumab-lenvatinib combination with median PFS 7.54 months (95% CI:2.6-11.5). ER positivity was associated with significant PFS benefit in both the ICI monotherapy group (11.9 vs. 0.63 months, p=0.061) and the group that received ICI/TKI combination (11.3 vs. 1.75 months, p=0.001). Analogous benefit was noted in the Overall Survival post start of IO or IO/TKI treatment (9.8 vs 0.6 months in MSI-high patients and 20.6 vs 5.9 months in MSS patients). ER-positivity remained an independent predictive factor favoring PFS in the Multivariate Cox regression analysis when adjusting for immunotherapy type, histology, and previous lines of therapy (HR=0.216, p=0.013). Conclusions: ER expression proved to be an independent prognostic factor regarding PFS in our cohort of patients. Further studies are needed to investigate the role of ER as a predictive biomarker for immunotherapy in EC. [Table: see text]
Gastrointestinal cancer trends in the Hispanic population: A SEER database population study (2000-2019).
Authors: Sharon Hechter, Ivan Nikiforov, David B. Greenberg
Journal: Journal of Clinical Oncology (2023)

e16331 Background: Cancer continues to be the leading cause of death in the Hispanic population. Gastrointestinal cancer surveillance data in Hispanic individuals has only recently become available in the last 3 decades. Differences in incidence rates among Hispanics and Non-Hispanic Whites (NHWs) need further elucidation. In this study, we analyzed trends in Hispanics and NHW populations across multiple gastrointestinal cancers. Methods: Gastrointestinal cancers (liver, colon and rectum, pancreas, esophagus, gallbladder, stomach, small intestine, anus, anal canal and anorectum) diagnosed between 2000-2019 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. We calculated incidence rates, confidence intervals and incidence rate ratios. Rates are per 100,000 and age adjusted to the 2000 US standard population. Rate ratios are the rounded rates in Hispanic individuals divided by the rounded rates in NHWs. Results: There was a higher incidence of liver, gallbladder, and stomach cancers among Hispanics when compared to NHWs between the years 2000-2019. Liver cancer incidence rate is (11.5 per 100,000) in Hispanics compared with (6.3 per 100, 000) in NHWs with an incidence rate ratio of 1.8. Gallbladder cancer incidence rate is (2.2 per 100,000) in Hispanics compared with (0.9 per 100,000) in NHWs with an incidence rate ratio of 2.4. Stomach cancer is (10.9 per 100,000) in Hispanics compared with (5.7 per 100,000) in NHWs with an incidence rate ratio of 1.9. The lowest incidence rate ratio was seen for anus, anal canal and anorectum cancers in Hispanics compared to NHWs. The incidence rate is (1.2 per 100,000) in Hispanics compared with (2.1 per 100,000) in NHWs with an incidence rate ratio of 0.6. Remaining cancers had incidence rate ratios less than 1.0 and were more likely to occur in NHWs. Conclusions: This study illustrates differing incidence rates of multiple gastrointestinal cancers among Hispanics compared to NHWs. Liver, gallbladder and stomach cancer incidence rates in Hispanics is double that of NHWs. Interestingly, the remaining gastrointestinal cancers had higher incidence rates among NHWs. Further research is warranted to understand the differences in cancer risk within the Hispanic population as well as healthcare access, language barriers and cultural differences that may play a role. [Table: see text]